WO2004007473A1 - Procede de preparation de paclitaxel - Google Patents

Procede de preparation de paclitaxel Download PDF

Info

Publication number
WO2004007473A1
WO2004007473A1 PCT/GB2003/003041 GB0303041W WO2004007473A1 WO 2004007473 A1 WO2004007473 A1 WO 2004007473A1 GB 0303041 W GB0303041 W GB 0303041W WO 2004007473 A1 WO2004007473 A1 WO 2004007473A1
Authority
WO
WIPO (PCT)
Prior art keywords
baccatin
process according
iii
paclitaxel
protecting group
Prior art date
Application number
PCT/GB2003/003041
Other languages
English (en)
Inventor
Dharmaraj Ramachandra Rao
Rajendra Narayanrao Kankan
Original Assignee
Cipla Limited
Wain, Christopher, Paul
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Limited, Wain, Christopher, Paul filed Critical Cipla Limited
Priority to GB0500809A priority Critical patent/GB2405637B/en
Priority to AU2003254450A priority patent/AU2003254450A1/en
Priority to AP2005003229A priority patent/AP2005003229A0/xx
Publication of WO2004007473A1 publication Critical patent/WO2004007473A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for preparing the chemotherapeutic agent paclitaxel.
  • Paclitaxel is a known antineoplastic compound which, if desired, can be isolated from the bark of Taxus brevifolia (Western Yew). Its chemical name is 5 ⁇ ,20-epoxy- l,2 ⁇ ,4,7 ⁇ ,10 ⁇ ,13 ⁇ -hexahydroxytax-l l-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. The chemical structure is shown below.
  • a process for preparing paclitaxel which process comprises the steps of a) acetylating 10-deacetyl baccatin El (I) at the C-10 position in the presence of a tertiary amine base to give baccatin -III (II); b) protecting baccatin-III (II) at the C-7 position by reacting baccatin-III with a protecting group; c) converting the product of step (b) to paclitaxel.
  • step (b) we prefer to use 2,2,2-trichloroethylchloroformate (Troc) as the protecting group.
  • Troc 2,2,2-trichloroethylchloroformate
  • the process of the invention proceeds first by acetylation of 10-deacetyl baccatin El at the C-10 position followed by protection at the C-7 position.
  • baccatin III and the C-7 protected baccatin III derivative are obtained in much greater yield than the intermediates obtained in previous processes.
  • the yield of baccatin El is basically quantitative - that is 100% yield, or very close to 100% yield.
  • the C-7 protected baccatin El derivative is also obtained in quantitative, or virtually quantitative yields (that is, 100% yield).
  • step (a) of the process surprisingly speeds up the reaction time of this step to about 1 hour or less and provides a very pure product in virtually quantitative yield.
  • Holton et al (Tetrahedron letters 39 (1998) 2883-2886) have reported on the selective protection of the C(7) and C(10) hydroxyl groups in 10-deacetyl baccatin El.
  • the maximum reported yield is 95% (using CeCl 3 and acetic anhydride) which is less than that achieved in the present invention.
  • addition of base is reported by Holton et al to induce the formation of 7-acetyl-lO-DAB and 7-acetyl baccatin III side products.
  • any suitable tertiary amine base can be used, for example any member of the trialkylamines (including isomers thereof), for example trialkylamines where each alkyl group is, independently, Q to do- Particularly good results have been achieved using triethylamine, so we prefer to use this compound, although similar compounds can be used.
  • the completion of the reaction within 1 hour or less contributes to an efficient and economical process, and provides considerable advantage for a commercial scale operation.
  • the acetylation in step (a) can be accomplished using any suitable method. For example, it can be done using acetic anhydride or acetyl chloride.
  • Acetic anhydride can, for example, be used in the presence of CeCl 3 or ZnCl or YbCl 3 employing an organic solvent system, such as tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • any suitable protecting group can be used in step (b), although we prefer to use 2,2,2- trichloroethylchloroformate (Troc).
  • Troc 2,2,2- trichloroethylchloroformate
  • the protecting groups used have required strongly acidic conditions for deprotection, and this results in a crude product with more impurities. In these circumstances, the product is difficult to purify and thus obtained in low yield. Use of Troc in particular avoids these difficulties and thus contributes to higher overall yields of product.
  • Other suitable protecting groups include carbobenzyloxycarbonyl, or t-butoxycarbonyl or 9-flurenyImethoxycarbonyl.
  • a catalyst is used to perform step (b). Any suitable catalyst may be used, although we prefer to use a 4-dimethylaminopyridine (DMAP). Other suitable tertiary amines such as triethyl amine, di-isopropyl ethyl amine, N,N-dimethyl aniline can be employed if desired.
  • DMAP 4-dimethylaminopyridine
  • Other suitable tertiary amines such as triethyl amine, di-isopropyl ethyl amine, N,N-dimethyl aniline can be employed if desired.
  • the use of a catalyst during step (b) helps ensure virtually quantitative yields of product with respect to baccatin-III.
  • step (b) is performed at less than room temperature (that is, less than about 25°C), preferably at less than 0°C. It is particularly preferred to use a low temperature of, for example, from -5°C to -15°C, suitably from -5°C to -10°C. We have found that the use of a low temperature during this step gives a fewer impurities than when the reaction is done at room temperature, and also reduces the reaction time. Low temperature conditions are particularly suitable when employing Troc as the protecting group.
  • step (b) it is also preferred during step (b) to add the protecting group in two or more lots during the reaction. This helps improve both the yield and purity of the product and, importantly, also reduces the reaction time for this step. Typically, the reaction time is reduced to about 1 hour for addition of two separate lots of protecting group. Addition of the protecting group in two or more lots is particularly preferred when Troc is used, as this gives very good results. For example, addition of Troc in two lots to baccatin El so as to give 7- Troc- baccatin IE, using DMAP as catalyst and a temperature of from -5°C to -15°C, gives a quantitative yield of 7-Troc-baccatin IE (that is, 100% yield), negligible impurities and a reaction time of 1 hour. Similar results are obtained using suitable catalysts other than DMAP.
  • the starting material, 10-deacetyl baccatin IE can be obtained according to known procedures. For example, it can, if desired, be obtained from the needles of Tax s baccata.
  • Step (c) involves converting the product of step (b), which is preferably 7-Troc- baccatin El, to paclitaxel, and this can be achieved by any suitable method.
  • step (c) involves coupling the product of step (b) with a suitable compound so as to give a ⁇ amido ester side chain at the C- 13 position, followed by deprotection at the C-7 position.
  • a suitable ⁇ - lactam such as, for example, N-benzoyl-3-triethylsilyloxy-4-phenyl azetidin-2-one in the coupling reaction.
  • a preferred process scheme is as follows:
  • step (c) The coupling reaction in step (c) is preferably carried out using 7-Troc-baccatin-EI and a racemic mixture of N-benzoyl-3-triethylsilyloxy-4-phenyl azetidine-2-one in the presence of n-butyl lithium. This is an efficient reaction and gives good stereoselectivity.
  • other methods of coupling a suitable ⁇ -amido ester side chain to the C-7 and C-10 protected baccatin-III intermediate can be used if desired.
  • a deprotection step is required following the coupling reaction. Any suitable method of deprotection may be used, although we prefer to avoid using harsh or strongly acidic conditions. Where 7-Troc deprotection is required, the deprotection can, for example, be carried out using zinc and acetic acid. It will be noted in the above illustrated scheme that deprotection occurs at both the C-7 position and in the side chain bearing the triethylsilyl (TES) group.
  • TES triethylsilyl
  • Paclitaxel made according to the process of the invention can be incorporated into pharmaceutical dosage forms including, but not limited to, capsules, tablets, infusion solutions/suspensions and injection concentrates. As will be clear to those skilled in the art, the above forms may be formulated using appropriate pharmaceutical excipients.
  • Example 1 The following Examples illustrate the invention: Example 1
  • the reaction was monitored by TLC (CH 2 Cl 2 /methanol 9:1).
  • the reaction mixture was diluted with 3.0 litres of MDC and washed with 3.0 litres of aqueous 0.5 N potassium bisulfate, water, saturated NaHCO 3 and brine.
  • the organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure.
  • the resulting white residue was sonicated in diethyl ether and filtered.
  • reaction was monitored by TLC (dichloromethane/methanol, 9:1).
  • the reaction mixture was diluted with 30 ml of dichloromethane and washed with 30 ml of aq. 0.5 N potassium bisulfate, water, saturated NaHCO 3 and brine.
  • the organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure.
  • the resulting white solid residue was sonicated in diethyl ether and filtered. Recrystallisation in methanol afforded 244 mg of 7-Troc-baccatin-IE, purity 82%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epoxy Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé permettant de préparer du paclitaxel. Ce procédé consiste (a) à acétyler du 10-deacétyl-baccatine III à la position C-10 en présence d'une base amine tertiaire pour obtenir la baccatine III; (b) à protéger la baccatine III à la position C-7 par réaction de la baccatine III avec un groupe protecteur; (c) à transformer le produit obtenu à l'étape (b) en paclitaxel. De préférence, le groupe protecteur à la position C-7 est 2,2,2-trichloroéthylchloroformate.
PCT/GB2003/003041 2002-07-15 2003-07-15 Procede de preparation de paclitaxel WO2004007473A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
GB0500809A GB2405637B (en) 2002-07-15 2003-07-15 Process for preparing of Paclitaxel
AU2003254450A AU2003254450A1 (en) 2002-07-15 2003-07-15 Process for preparing of paclitaxel
AP2005003229A AP2005003229A0 (en) 2002-07-15 2003-07-15 Process for preparing of paclitaxel.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0216412.7 2002-07-15
GBGB0216412.7A GB0216412D0 (en) 2002-07-15 2002-07-15 Chemical process

Publications (1)

Publication Number Publication Date
WO2004007473A1 true WO2004007473A1 (fr) 2004-01-22

Family

ID=9940483

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2003/003041 WO2004007473A1 (fr) 2002-07-15 2003-07-15 Procede de preparation de paclitaxel

Country Status (6)

Country Link
AP (1) AP2005003229A0 (fr)
AU (1) AU2003254450A1 (fr)
GB (2) GB0216412D0 (fr)
RU (1) RU2326876C2 (fr)
WO (1) WO2004007473A1 (fr)
ZA (1) ZA200501234B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008116387A1 (fr) * 2007-03-27 2008-10-02 Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences Procédé de fabrication de taxol et de dérivés de taxol
EP2147916A4 (fr) * 2004-01-16 2010-01-27 Guilin Huiang Biochemistry Procede de preparation des taxanes de synthese
JP2012126723A (ja) * 2010-12-13 2012-07-05 Yung Shin Pharmaceutical Industrial Co Ltd ルイス酸触媒を使用してバッカチン誘導体からタキソイドを調製するための方法
CN104250235A (zh) * 2014-09-24 2014-12-31 江苏红豆杉药业有限公司 一种紫杉醇的制备方法
CN105418543A (zh) * 2015-12-01 2016-03-23 贵州大学 从南方红豆杉植物中提取巴卡亭iii对照品的方法
CN109438395A (zh) * 2018-12-25 2019-03-08 重庆市碚圣医药科技股份有限公司 一种紫杉醇中间体的合成方法及其产品

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017656A1 (fr) * 1996-10-24 1998-04-30 Institute Armand-Frappier Famille de taxanes canadensol, preparation semi-synthetique et usage therapeutique de ces derniers
WO1999045001A1 (fr) * 1998-03-02 1999-09-10 Bristol-Myers Squibb Company Synthese de paclitaxel a partir de baccatine iii par protection du 7-hydroxyle au moyen d'une base forte et d'un electrophile

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998017656A1 (fr) * 1996-10-24 1998-04-30 Institute Armand-Frappier Famille de taxanes canadensol, preparation semi-synthetique et usage therapeutique de ces derniers
WO1999045001A1 (fr) * 1998-03-02 1999-09-10 Bristol-Myers Squibb Company Synthese de paclitaxel a partir de baccatine iii par protection du 7-hydroxyle au moyen d'une base forte et d'un electrophile

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
F. GUERITTE-VOGELEIN: "CHEMICAL STUDIES OF 10-DEACETYL BACCATIN III.", TETRAHEDRON., vol. 42, no. 16, 1986, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL, pages 4451-60, XP002025601, ISSN: 0040-4020 *
KOICHIRO MORIHIRA: "ENANTIOSELECTIVE TOTAL SYNTHESIS OF TAXOL", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 120, no. 49, 1998, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., US, pages 12980 - 1, XP000788257, ISSN: 0002-7863 *
R.A. HOLTON: "SELECTIVE PROTECTION OF THE C(7) AND C(10) HYDROXYL GROUP IN 10-DEACETYL BACCATIN III", TETRAHEDRON LETTERS., vol. 39, no. 19, 1998, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL, pages 2883 - 6, XP004115707, ISSN: 0040-4039 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2147916A4 (fr) * 2004-01-16 2010-01-27 Guilin Huiang Biochemistry Procede de preparation des taxanes de synthese
EP2147916A1 (fr) * 2004-01-16 2010-01-27 Guilin Huiang Biochemistry Procede de preparation des taxanes de synthese
US8314261B2 (en) 2004-01-16 2012-11-20 Guilin Huiang Biochemistry Pharmaceutical Co. Ltd. Process for the preparation of synthetic taxanes
WO2008116387A1 (fr) * 2007-03-27 2008-10-02 Dalian Institute Of Chemical Physics, Chinese Academy Of Sciences Procédé de fabrication de taxol et de dérivés de taxol
JP2012126723A (ja) * 2010-12-13 2012-07-05 Yung Shin Pharmaceutical Industrial Co Ltd ルイス酸触媒を使用してバッカチン誘導体からタキソイドを調製するための方法
CN104250235A (zh) * 2014-09-24 2014-12-31 江苏红豆杉药业有限公司 一种紫杉醇的制备方法
CN104250235B (zh) * 2014-09-24 2016-10-05 江苏红豆杉药业有限公司 一种紫杉醇的制备方法
CN105418543A (zh) * 2015-12-01 2016-03-23 贵州大学 从南方红豆杉植物中提取巴卡亭iii对照品的方法
CN109438395A (zh) * 2018-12-25 2019-03-08 重庆市碚圣医药科技股份有限公司 一种紫杉醇中间体的合成方法及其产品

Also Published As

Publication number Publication date
GB2405637A (en) 2005-03-09
AP2005003229A0 (en) 2005-03-31
AU2003254450A1 (en) 2004-02-02
ZA200501234B (en) 2006-10-25
RU2005102395A (ru) 2006-06-10
GB2405637B (en) 2006-02-22
GB0216412D0 (en) 2002-08-21
RU2326876C2 (ru) 2008-06-20
GB0500809D0 (en) 2005-02-23

Similar Documents

Publication Publication Date Title
JP3519084B2 (ja) β−ラクタムおよびアンモニウムアルコキシドから合成したタキサン
JP3394284B2 (ja) 金属アルコキシド及びオキサジノンを用いたタキサン誘導体の半合成
EP1170293B1 (fr) Procédé de dérivatisation selective de taxanes
US8293930B1 (en) One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel
US20070027332A1 (en) Semi-synthetic conversion of paclitaxel to docetaxel
CA2211799C (fr) Preparation de taxol et de docetaxel a l'aide d'amines primaires
HU209299B (en) Process for producing taxol with utilizing oxazion
EP1814868B1 (fr) Semi-synthese d'intermediaires de taxanes et leur conversion en paclitaxel et docetaxel
CA2634453A1 (fr) Nouveaux composes et procedes servant a former des taxanes et utilisation de ceux-ci
JP2009531446A (ja) タキサン誘導体の合成のためのコンバージェントプロセス
EP1732911A2 (fr) Semi-synthese d'intermediaires de taxane et d'analogues d'aziridine et leur transformation en paclitaxel et en docetaxel
JP3940392B2 (ja) Ｃ７タキサン誘導体およびそれを含有する薬剤組成物
ZA200501234B (en) Process for preparing paclitaxel
EP1727810B1 (fr) Semi-synthese d'intermediaires taxane a partir de 9-dihydro-13-acetylbaccatine iii
US5760251A (en) Taxol process and compounds
KR20010102444A (ko) 10-데아세틸바카틴 ⅲ으로부터 탁산류의 제조 방법
JP3892480B2 (ja) Ｃ９タキサン誘導体およびそれを含有する薬剤組成物
JP3445973B2 (ja) パクリタクセルおよびその類似体の半合成に有用な中間体ならびに方法
US6242614B1 (en) Semi-synthesis of paclitaxel using dialkyldichlorosilanes
KR20030055332A (ko) 파클리탁셀의 제조방법
WO2008032104A1 (fr) Synthèse en un creuset de dérivés de taxane et leur conversion en paclitaxel et docétaxel
EP1370541B1 (fr) Procede de preparation de paclitaxel (taxol) utilisant un acide 3-(alk-2-ynyloxy) carbonyl-5-oxazolidine carboxylique
KR101379694B1 (ko) 탁산유도체의 제조방법
WO2009137084A2 (fr) Processus de préparation des taxanes et de leurs intermédiaires

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 0500809

Country of ref document: GB

Kind code of ref document: A

Free format text: PCT FILING DATE = 20030715

WWE Wipo information: entry into national phase

Ref document number: 46/MUMNP/2005

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 2005102395

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 200501234

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: AP/P/2005/003229

Country of ref document: AP

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Ref document number: JP